The survival of an organism during protein starvation depends on the capacity of the system to regulate protein breakdown. Although recent insights on the control of protein degradation have been obtained from bacteria, a direct attack on the problem can best be undertaken using the more readily isolatable proteases of mammalian cells. It is our contention that protein degradation is regulated by the accumulation of uncharged tRNA and 3',5'-cyclic AMP which interact at a membrane associated complex to control the levels of a unique nucleotide, guanosine tetraphosphate (ppGpp), which in turn modifies the activity of intracellular proteases. The experiments detailed in this proposal are designed to demonstrate the presence of this nucleotide in mammalian systems during starvation and to assess its regulatory function in protein degradation.